Project Summary The elderly have increased susceptibility to periodontitis, a prevalent inflammatory disease that causes destruction of the tooth-supporting tissues (periodontium). This increased susceptibility is likely caused by alterations to the immuno-inflammatory status and/or regenerative potential of the periodontal tissue. Impaired tissue regeneration may be traced back to age-related alterations in the mesenchymal stem cell (MSC) niche of the periodontal ligament (PDL), harboring the osteoprogenitors. Del-1 is a homeostatic protein secreted by distinct tissue resident cells: It regulates the recruitment of neutrophils (endothelial cell-derived Del-1) and the efferocytosis of apoptotic neutrophils (macrophage-derived Del-1), thus Del-1 controls both the initiation and resolution of inflammation. Additional research has shown that Del-1 is produced in the PDL and promotes osteoblastic differentiation as well as induces the formation of new alveolar bone during resolution of experimental periodontitis. However, Del-1 expression is severely diminished in old age. This project investigates the overarching hypothesis that the aging-related Del-1 deficiency may contribute to the dysregulation of osteogenesis, thereby leading to defective periodontal bone regeneration in old age. This proposal comprises two specific aims and focuses on relevant animal model-based mechanistic and intervention studies, including mice with lineage-specific deletions or overexpression of Del-1 or its receptor β3 integrin. In Aim 1, it is proposed that Del-1 promotes osteoblastic differentiation by acting via its RGD motif on β3 integrin in osteolineage progenitors. Aim 2 involves the elucidation of the mechanisms by which Del-1 regulates osteogenesis in vivo and, moreover, examines the consequences of aging-related Del-1 deficiency on bone regeneration. It is also proposed that impaired bone regeneration in old mice can be reversed by local administration of Del-1. On the basis that the regenerative defect of the aged PDL-MSC niche is reversible and regulated by the extrinsic microenvironment, the findings of this proposal may potentially pave the way to novel Del-1-based approaches to rejuvenate niche functionality and thus enhance periodontal bone regeneration in old age.